Microglia are the resident myeloid cells in the central nervous system (CNS) and the key player of CNS immunity. Excessive and persistent activation of microglia has been implicated in many neurological disorders including neurodegenerative diseases and multiple sclerosis (MS). However, how microglia activation/deactivation is regulated remains poorly understood. Based on our recent findings, we propose that caspase-8 is a key modulator for microglial cell activation and CNS inflammation. Besides its canonical function in initiating the extrinsic pathway of apoptosis, caspase-8 possesses non-apoptotic functions in regulating activation, differentiation and survival of peripheral immune cells. In the CNS, we found that microglia are the predominant cells expressing caspase-8, indicating that caspase-8 may control CNS immunity by regulating microglia activation status and survival. Our preliminary data demonstrate that conditional deletion of Casp8 in myeloid cells including microglia results in exacerbated neuroinflammation in animal models of MS, and that caspase-8-deficient microglia exhibit enhanced proinflammatory responses in vitro and in cultured brain slices. We hypothesize that caspase-8 is a gatekeeper that restricts microglia/macrophage activation and that dysregulation of microglial activation may perpetuate pathological CNS inflammatory responses and impair myelin repair. In this proposal, we will employ molecular and genetic approaches to determine the mechanism by which caspase-8 regulates microglial activation and inflammatory responses in vitro and in vivo. This study represents the first to unravel the previously unrecognized immune function of caspase-8 in CNS demyelination and remyelination. Insights gained from this study are likely to provide not only new perspectives for the pathogenesis of MS, but also have implications in many other neurodegenerative diseases where chronically activated microglia/macrophages are part of pathological features.